m ⁶ A‐Mediated IGF1 Hypomethylation Impairs Decidualization and Promotes Preeclampsia Pathogenesis: Implications for Epigenetic Therapy

The decidua, a dynamic and heterogeneous maternal tissue essential for pregnancy maintenance, has emerged as a key contributor to preeclampsia (PE) pathogenesis. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq), we profiled N6-methyladenosine (m⁶A) methylation patterns and mRNA expression in the decidua of early-onset PE (EPE), late-onset PE (LPE), and normal pregnancy (NP) samples. Integrated analysis revealed that differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were significantly enriched in pathways critical for decidualization, including HIF-1, PI3K-AKT, and Rap1 signaling. These pathways exhibited concurrent m⁶A methylation and expression changes, implicating their involvement in PE development. Notably, insulin-like growth factor (IGF1) was hypomethylated and downregulated in PE decidua compared to NP controls. Given IGF1's central role in stromal cell differentiation and decidualization, its dysregulation likely impairs normal decidual function. Validation using external datasets, quantitative PCR, and siRNA knockdown in human endometrial stromal cells confirmed reduced IGF1 expression and its impact on decidual markers like prolactin. Our findings demonstrate that disrupted m⁶A methylation impairs decidualization via IGF1 regulation, offering novel mechanistic insight into PE. This study highlights the importance of epitranscriptomic regulation at the maternal-fetal interface and identifies m⁶A-modified transcripts as potential therapeutic and diagnostic targets in PE.